Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 41, Issue 7, Pages 2040-2051Publisher
WILEY
DOI: 10.1002/eji.201041316
Keywords
Anti-oxidant response; Atherosclerosis; Inflammation; Interleukin-1; Nrf2
Categories
Funding
- Swiss National Science Foundation [310030-124922/1]
- Swiss Federal Institute of Technology Zurich [ETH-18 09-1]
- Grants-in-Aid for Scientific Research [19GS0312] Funding Source: KAKEN
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Oxidative stress and inflammation - two components of the natural host response to injury - constitute important etiologic factors in atherogenesis. The pro-inflammatory cytokine interleukin (IL)-1 significantly enhances atherosclerosis, however, the molecular mechanisms of IL-1 induction within the artery wall remain poorly understood. Here we have identified the oxidative stress-responsive transcription factor NF-E2-related 2 (Nrf2) as an essential positive regulator of inflammasome activation and IL-1-mediated vascular inflammation. We show that cholesterol crystals, which accumulate in atherosclerotic plaques, represent an endogenous danger signal that activates Nrf2 and the NLRP3 inflammasome. The resulting vigorous IL-1 response critically depended on expression of Nrf2, and Nrf2-deficient apolipoprotein E (Apoe)(-/-) mice were highly protected against diet-induced atherogenesis. Importantly, therapeutic neutralization of IL-1 alpha and IL-1 beta reduced atherosclerosis in Nrf2(+/-) Apoe(-/-) but not in Nrf2(-/-) Apoe(-/-) mice, suggesting that the pro-atherogenic effect of Nrf2-signaling was primarily mediated by its permissive role in IL-1 production. Our studies demonstrate a role for Nrf2 in inflammasome activation, and identify cholesterol crystals as disease-relevant triggers of the NLRP3 inflammasome and potent pro-atherogenic cytokine responses. These findings suggest a common pathway through which oxidative stress and metabolic danger signals converge and mutually perpetuate the chronic vascular inflammation that drives atherosclerosis.
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